This application is the national phase under 35 U.S.C. xc2xa7 371 of PCT International Application No. PCT/CN00/00010 which has an International filing date of Jan. 21, 2000, which designated the United States of America and was not published in English.
1. Field of the Invention
This invention relates to new Gymnemic acid derivatives, their preparation, pharmaceutical composition or extract which contains them, and their medical use, especially the use in the prevention or treatment of the diseases associated with hyperglycemia, hyperlipidemia and platelets aggregation.
2. Background of the Related Art
A lot of studies on Gymnemic Acid derivatives have been done and all of these Gymnemic acid derivatives are from the plant called Gymnema cane, which is classified as Gymnema sylvestre. R. Br. In India, it has been used to treat swelling, snake venom toxin, malaria, as a diuretic or to lower blood sugar level. Yet the Gymnemic acid derivatives and their biological activity mentioned in this invention haven""t been reported up to this date.
The object of this invention is to find new Gymnemic acid derivatives and develop their medical use.
The inventors have found out new Gymnemic acid derivatives of formula I or II and also their medical use, especially in treating hyperglycemia, hyperlipidemia and platelets aggregation. The invention is now performed based on the discovery mentioned above.
In the first part, this invention concerns Gymnemic Acid derivatives formula I or II, 
wherein, R1 is H or the radical represented by the following formula 
R3 is H, and R2 symbolizes the following radical, 
or R3 symbolizes the following radical, 
and R2 is H or the following radical, 
or a pharmaceutical base addition salt thereof.
The second part of this invention relates to pharmaceutical composition which contains at least one kind of Gymnemic Acid derivative of formula I and/or II or pharmaceutical base addition salt thereof as active ingredient, pharmaceutical carrier and excipient.
The third part of the invention involves Gymnemic Acid extract 12.5-40 wt % of which is Gymnemic Acid derivative of formula l and/or II.
Another part of this invention relates to pharmaceutical composition for the prevention or treatment of the diseases associated with hyperglycemia, hyperlipidemia and platelets aggregation, which contains at least one kind of gymnemic acid derivative of formula I and/or II or pharmaceutical base addition salt thereof as an active ingredient, pharmaceutical carrier and excipient.
Another part of the invention relates to a pharmaceutical composition for the prevention or treatment of diabetes, which includes at least one kind of Gymnemic Acid derivative of formula I and/or II or pharmaceutical base addition salt thereof as an active ingredient, a pharmaceutical carrier and an excipient.
Another part of this invention relates to a pharmaceutical composition for the prevention or treatment of higher blood lipid level, which contains at least one kind of gymnemic acid derivative of formula I and/or II or a pharmaceutical base addition salt thereof as an active ingredient, pharmaceutical carrier and an excipient.
Another part of this invention relates to pharmaceutical composition for the prevention or treatment of platelets aggregation, which contains at least one kind of gymnemic acid derivative of formula I and/or II or pharmaceutical base addition salt thereof as an active ingredient, pharmaceutical carrier and excipient.
Another part of this invention relates to the preparation of Gymnemic Acid derivative of formula I and If or pharmaceutical base addition salt thereof, which includes the following steps:
a) extracting the plant Gymnema cane with ethane under reflux and then concentrating;
b) extracting concentrated liquid in step a) with cyclohexane, then extracting with n-butanol, concentrating to dryness under reduced pressure, and then obtaining a paste;
c) subjecting the paste in step b) to silica column chromatography with chloroform:methanol=90:10-50:5 or 90:10-60:40 (v/v) as elute, obtaining gymnemic acid derivative of formula I and residue;
d) subjecting the residue in step c) to C18 column chromatography with methanol/water=20/80xe2x88x9240/60 (v/v) as eluant, obtaining gymnemic acid derivative of formula II;
e) if desired, converting the obtained gymnemic acid derivative of formula I or II into pharmaceutical base addition salt with an inorganic or organic base.
Another part of this invention relates to a method of preparation of the extract containing Gymnemic Acid derivative of formula I and II which ranges from 12.5-40 wt %, which includes the following steps:
a) extracting Gymnema cane leaves with 60-95% ethanol and concentrating,
b) extracting concentrated liquid in step a) with cyclohexane, then extracting with n-butanol, and then concentrating the extract under reduced pressure.
Another aspect of the invention relates to use of Gymnemic Acid derivative of formula I and II or the extract containing Gymnemic Acid derivative of formula I and II for the manufacture of medicament for the prevention or treatment of the diseases and conditions associated with hyperglycemia, hyperlipidemia and platelets aggregation.
Finally, this invention relates to the method of preventing or treating the diseases and conditions associated with hyperglycemia, hyperlipidemia and platelets aggregation, which includes administrating a prophylactic or effective quantity of Gymnemic Acid derivative of formula I and II to a patient suffering from diseases or conditions associated with hyperglycemia, hyperlipidemia and platelets aggregation.
The term xe2x80x9cpatientxe2x80x9d in the invention refers to a mammal, including a human being, and especially a human being.
This invention relates to Gymnemic Acid derivative of formula I and II, 
wherein, R1 is H or the radical represented by the following formula 
R3 is H, and R2 is the following group, 
or R3 is the following group, 
and R2 is H or the following group, 
or the pharmaceutical base addition salt.
According to the invention, the pharmaceutical base addition salt of Gymnemic acid of formula I or II includes a salt formed with pharmaceutical inorganic or organic base. The inorganic base, for example, includes alkali or alkali earth metal hydroxide, alkali metal or alkali earth metal carbonate or bicarbonate, alkali metal may be selected from Li, Na, K, alkali earth metal may be selected from Ba, Mg, Ca etc. The organic base, for example, may be triethyl amine etc.
According to this invention, the Gymnemic acid compound preferably is a
According to the invention, the Gymnemic acid compound is preferably a Gymnemic Acid compound of formula I wherein R1 is the following radical. 
According to the invention, the Gymnemic acid compound is preferably a Gymnemic Acid compound of formula II wherein R3 is H and R2 is the following radical. 
According to the invention, the Gymnemic acid compound is preferably a Gymnemic Acid compound of formula II wherein R3 is H and R2 is the following radical. 
According to the present invention, the Gymnemic acid compound is preferably a Gymnemic Acid compound of formula II wherein R3 is the following radical and R2 is H. 
According to the invention, the Gymnemic acid compound is preferably Gymnemic Acid compound of formula II wherein both R3 and R2 are the following radicals respectively. 
According to the invention, the pharmaceutical composition contains at least one kind of Gymnemic Acid derivative of formula I and/or II, a pharmaceutical carrier and an excipient. For example, the pharmaceutical composition may include, for example, 1.25-2.10 wt % compound A, 0.89-1.5 wt % compound B, 2.40-3.80 wt % compound C, 2.10-3.40 wt % compound D, 2.74-4.60 wt % compound E, and 3.24-5.4 wt % compound F (compounds A, B, C, D, E and F as defined in examples below.). This pharmaceutical composition can be. administrated by gastrointestinal, parenteral or topical administration, such as oral, muscle, subcutaneous, peritoneum, vein etc. The forms of the drug suitable for gastrointestinal administration are for example tablet, capsule, solution, suspension, powder, granules, etc. The forms of the drug suitable for parenteral include injection solution, freeze-dried powder for injection preparations, etc. The drug forms suitable for the topical use are for example, an ointment, cream, paste, patch, and spray. Of all these forms, oral administration is preferred, and a capsule is the preferred be oral form. The pharmaceutical carrier or excipient of the pharmaceutical composition includes binding agent, filling material, wetting agent, disintegrating agent, surfactant, lubricating agent, diluting agent, etc. If desired, a coloring agent, flavoring agent, solubilizer, buffer, etc are also used. The diluting agents in the invention include starch, dextrin, lactose, microcrystalline cellulose, silica gel, etc. Silica gel is preferred. The wetting agents includes water and ethanol. Lubricating agents include talcum powder, and magnesium stearate.
The pharmaceutical composition in the present invention can be produced by the known methods in this art. For example, by mixing Gymnemic Acid derivative of formula I and/or II or pharmaceutical base addition salt with pharmaceutical carrier and excipient.
The dose of Gymnemic Acid derivative of formula I and II depends on many factors such as the character and seriousness level of the disease to be prevented or treated, sex, age, weight, individual response, specific compound, administration route and times of administration. Generally the specific dose depends on the judgment of the physician. Generally speaking, the dosage of the pharmaceutical composition Gymnemic Acid derivative of formula I and II can be in the form of single dose and taken 1-4 times per day.
According to this invention, the derivative or pharmaceutical base addition salt of formula I Gymnemic Acid can be prepared as follows:
a) crushing dry leaves of Gymnema cane, then extracting three times with 60-95% ethanol under reflux, two hours for each, combining extracted liquid and concentrating under reduced pressure until there was no ethanol;
b) extracting the concentrated mixtures in step a) for 3 to 6 times with cyclohexane, then extracting with n-butanol, concentrating to dryness under reduced pressure, obtaining dry extract;
c) subjecting the dry extracts in step b) to silica gel column chromatography with a mixture of chloroform and methanol at a ratio of 90:10 to 60:40 (v/v) as eluant, and obtaining derivatives of formula I,
d) If desired, converting the derivative of formula I in step c) into pharmaceutical base addition salt thereof.
According to this invention, the gymnemic acid derivative of formula II can be prepared as follows:
a) Crushing dry leaves of Gymnemacane, then extracting three times with 60-95% ethanol under reflux, two hours for each, combining extracted liquid and concentrating under reduced pressure until there was no ethanol;
b) extracting concentrated mixtures for 3 to 6 times with cyclohexane, then extracting with n-butanol; concentrating to dryness under reduced pressure;
c) mixing the dry extracts in step b) with rough silica gel; subjecting separation with thin layer chromatography of silica gel H with a mixture of chloroform and methanol at a ratio of 90:10 to 50:50 (v:v) as eluant, subjecting the residue after elution to C18 column chromatography with the eluant being methanol/water (20:80-40:60), and obtaining a derivative of formula II;
d) if desired, converting the derivative of formula II in step c) into the pharmaceutical base addition salt thereof.
According to this invention, the extract products with 12.5-40 wt % Gymnemic Acid derivative of formula I and formula II can be prepared as follows: raw powder of Gymnema cane leaves were refluxed 1-4 times with 60-95% ethanol, the amount of solvent for each is 6 ml/g, and the extraction time is 1-3 hours. The extract mixtures were combined together and distilled under reduced pressure till there was no ethanol, the concentrated mixture was extlacted with cyclohexane for 1-3 times, 500 ml of solvent was used each time. Then the mixture was extracted for 1-3 times with 500 ml n-butanol, all the extract mixtures were combined and distilled under reduced pressure to obtain the desired product.